CS215580B1 - 5,5-disubstituted barbituric acid - Google Patents

Description

The present invention relates to 5- (5-substituted) -burbituric acids of formula (I):

NH 0

wherein R ^{* 1} represents alkyl of 1 to 14 carbon atoms, allyl, propargyl or phenyl and H is hydroxy or a residue of an amide bonded glycine ethyl ester. These compounds are novel, not yet described in the literature.

Depending on the operating conditions of any of the processes described below, the new derivatives of formula (I) may be assigned one of the corresponding tautomeric structures and / or the like. it may be a mixture of tautomer C).

The compounds of formula I are analogous

215 580

2.

and 5 '(2-amino-6-hydroxy-4-oxo-3,4-dihydro-pyrimidin-3-yl) -teromers of formula II,

ch ₂ ch ₂ ch ₂ ch ₂ cooh (II) which exhibits a significant therapeutic effect in welds and some transplanted tumors and is a suitable, practically non-toxic means for treating human cancer. The compound of formula II in combination with a number of clinically used cytostatics enhances their therapeutic effect without increasing the toxic effects of the cytostatic used. It also enhances the anti-leukemic effect of cyclopoephamide e-5-fluorouracil and other cytostatics (M. Semonaki et al., Cancer Chemotherapy, Pt.2, g, 107, 1976; V. Pujman et al., Neoplaama 2g, 85, +979; Certificate No. 176667) ·

The compounds of formula I showed a 5-fluorine recil enhancement effect, tested using La leukemia, inoculated to male Bleek C _g7 mice weighing 18-25 g in a bioassay. The test compounds were administered ac on day 3 after leukemia cell transplantation ( 20.1 () 6), _{in the} f _orm g of aqueous suspensions. After administration of the compound, an aqueous solution of 5-fluorouracil ac at a dose of 75 or 50 mg / kg was indicated to mice at 60 or 90 min intervals. The efficacy of the substances was assessed by the change in median survival in the experimental groups compared to the untreated control. The number of mice ranged from 8 to 11 per group. The experimental groups were treated with certain doses of the compound alone, a combination of the compound and 5-fluororaeil at a certain dose ratio and 5-fluorouracil alone. Changes in median survival were expressed in% above the value of 5-fluorouroil alone, whose median survival of 10 to 12 days was considered 100%. The median of untreated controls was 7 to 9 days. The compounds of formula I in the dose range of 20 to 250 mg / kg did not affect the spillover of treated animals. Combination of some substances with 5-fluorouracil at the appropriate dose ratio produced survival of the test animals over 5-fluorouracil alone, i.e. the investigated compounds showed a potency of 5-20% in animals and La leukemias of 10-20%.

In the screening for antineoplastic activity, the compounds of formula I exhibited a mild antineoplastic effect in animals and experimental tumors, at a dose range of 100 to 200 mg / kg p.o., showing a reduction in tumor size of up to 27%, without affecting the survival time of the animals. The 5-butyl-5- (4-carboxybutyl) berbituric acid ethoxycarbonylmethylamide showed the most pronounced effect at 200 mg / kg p.o. in S 37 sarcoma mice with a tumor size reduction of 27%, and 5-butyl 15- (4-carboxybutyl) barbituric acid in a tumor size reduction of 25% in aa 37 sarcoma and sarcoma mice using the same route of administration. The test substances ae appeared non-toxic.

The compounds of formula (I) are also intermediates for the synthesis of other pharmacologically active substances, in particular from the group of substances having an antineopleetic and potentiating effect.

The compounds of formula (I) may be prepared by methods generally known in the art. For example, a compound of formula I in which R is as defined above and R is hydroxy may be obtained from compounds of formula III,

R ³ OOC. 'r ¹ X

R ³ OOC ^z ' ^Sk (CH ₂ I ₄ COOR ³ (III) in which R · * ^- contaminates the same as in formula I e R ³ denotes a methyl or ethyl group, by a concentration of at least 1 mol equivalent of urea of formula IV nh ₂ o = c <

NH ₂ (IV) in anhydrous medium in the presence of sodium alcoholate, preferably ethylate or methylate, whereupon the crude condensation product is saponified with an aqueous alkali metal hydroxide solution.

T 2

A compound of formula I wherein R is as defined above and R is a group of formula V,

-NHCH ₂ COOC ₂ H ₅ (v)

For example, T 2 can be prepared from a compound of formula I wherein R is as defined above and R is hydroxy by reaction with glycine ethyl ester hydrochloride using amide bond reagents, preferably ethyl chloroformate and triethylamine, in methylene chloride.

The intermediates of formula (III) are in part known and in part not yet described. They can all be prepared, mostly in very good yield, by the same method, for example, the method described for the synthesis of alpha-carboxypimelic acid triethyl ester, which is required for the preparation of the compound of formula II (P. Karrer et al., Helv. Chim. Acta 2J, 237, 1944), i.e. by alkylating the compounds of formula VI,

R ³ OOC. R ¹ c ^{z z} \ ^J R OOC Na (VI) where R ¹ e R ³ have the abovementioned meaning, methyl or ethyl ester of delta-bromvelerové.

Further details of the preparation of the compounds of formula (I) are given in the following examples. Melting points refer to crystalline solvent-free substances and are not corrected. .

Example 1

5-Ethyl-5 '(4-kerboxybutyl) barbituric acid

To a solution of sodium ethylate, prepared by dissolving 3.45 g (0.15 md) of sodium in 150 ml of ethanol, add 9.00 g (0.15 mol) of urea and stir the reaction mixture for 10 minutes, add 15.82 g. (0.05 mol) alpha-ethyl-alpha-carboxypimelic acid triethyl ester and the reaction mixture was refluxed from stirring for 4 hours and then left overnight at room temperature. After distilling off the ethanol in a water pump vacuum and adding 25 ml of water to the evaporator, acidify with dilute hydrochloric acid (1 L) to pH 2. The precipitate is filtered off with suction, washed with water and dried to constant weight at room temperature. There were obtained 8.58 g of 5-ethyl-5- (4-carbo «xybutyl) berbiturové that after kyystalizaei from water to give a product of mp 205-207 ⁰

In an analogous manner, the appropriate trieaters &quot; phenylalpha-carboxypimel and urea, and prepare the following:

5-methyl-5- (4-carboxybutyl) barbituric acid, m.p. 185 DEG C. and 187 DEG C. (water); □ 5-propyl-5 (4-carboxybutyl) barbituric acid, m.p. 182-184 ° C (water-ethanol, 1: 1), □ 5-butyl-5- (4-carboxybutyl) berbituric acid, m.p. 192-194 ° C (water-ethanol, 1: 1), 5-phenyl-5- (4-carboxybutyl) berbituric acid, m.p. 206 DEG -208 DEG C. (ethanol); 5-allyl-5- (6-carboxybutyl) berbituric acid, m.p. 150-152 ° C (water-ethanol, 1: 1).

Example 2

5-Butyl-5- (4-carboxybutyl) barbituric acid ethoxycarbonylmethylamide.

To a solution of 1.14 g (0.004 mol) of 5-butyl 1-5- (4-carboxybutyl) barbituric acid in 20 ml of anhydrous methylene chloride and 0.41 g (0.004 mol) of triethylamine cooled to -10 ° C was added 0.46 g (0.004 mol) of ethyl chloroformate and after 15 minutes 0.56 g (0.004 mol) of glycine ethyl ester hydrochloride and 1.62 g (0.016 mol of triethylamine) are added and the reaction is stirred at room temperature for 1 hour. After evaporation of the volatiles in a water-jet vacuum, 20 ml of water and 3 ml of acetic acid are added to the residue, the precipitate is filtered off, washed with water and dried to constant weight to give 1.09 g of 5-butyl-5- ( 4-carboxybutylbituric acid, having a crystallization from 50% aqueous ethanol, mp 173-174 ° C.

In an analogous manner using 5-ethyl-5- (4-carboxybutyl) barbituric acid, 5-ethyl-5- (4-carboxybutyl) barbituric acid ethoxycarbonylmethylamide was prepared, m.p.

155 DEG-157 DEG C. (ethanol-cyclohexane, 1: 1).

Claims (9)

SUBJECT OF THE INVENTION 1, 5,5-aubstituted berbituric acid of the formula I, (I) Wherein R is alkyl and 1 to 4 carbon atoms, allyl, propergyl or phenyl and R is hydroxy or an amide bonded glycine ethyl ester residue. 2. 5-Methyl-5- (4-carboxybutyl) berbituric acid. 3. 5-Ethyl-5- (4-carboxybutyl) berbituric acid. 4. 5-Propyl-5- (4-carboxybutyl) berbituric acid. 5. 5-Butyl-5- (4-carboxybutyl) barbituric acid. 6. 5-Phenyl-5- (4-carboxybutyl) barbituric acid. 7 5-Allyl-5- (4-carboxybutyl) berbituric acid. 8. 5-Ethyl-5- (4-carboxybutyl) -berbituric acid ethoxycarbonylmethylamide. 9 5-Butyl-5- (4-carboxybutyl) -berbituric acid ethoxycarbonylmethylamide. The invention relates to 5,5-disubstituted berbituric acids of general formula 1, HO In which R pollutes alkyl of 1 to 4 carbon atoms, ellyl, propergyl or phenyl with R is a hydroxy group or a residue of an amidically linked glycine ethyl ester. These novel, practically non-toxic substances show significant potentiating effects in known and clinically used cytostatics in animal experiments with experimental tumors: they are also useful as valuable intermediates in the synthesis of longer pharmacodynemically active compounds.